The g.-469G>A polymorphism in the GPIHBP1 gene promoter is associated with hypertriglyceridemia and has an additive effect on the risk conferred by LPL defective alleles

Abstract 

Background and aims

Hypertriglyceridemia (hyperTG) is a component of the metabolic syndrome and a cardiovascular or pancreatitis risk factor. Although both genetic and environmental factors influence its expression, the biological component of hyperTG is still underestimated and has been reported in 10–20% of cases only. Given its key role in the lipolysis of TG-rich lipoproteins, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) is a biological candidate for hyperTG. The aim of this study was to assess the association of new GPIHBP1 gene variants with hyperTG (fasting plasma TG values≥2.0mmol/L).

Methods and results

Sequencing the GPIHBP1 gene identified a g.-469G>A (rs72691625) polymorphism in the promoter. A sample of 541 Caucasians (263 normoTG and 278 hyperTG) was then screened for this polymorphism using a 5′nuclease TaqMan. In multivariate analyses, GPIHBP1 g.-469G>A polymorphism carriers were at significantly higher risk of hyperTG (≥2.0mmol/L) than non-carriers, the odds ratio (OR) being 1.67 (p=0.025) among heterozygotes and 5.70 (p=0.004) in homozygotes. The simultaneous presence of loss-of-function LPL polymorphisms had an incremental additive effect on the risk of hyperTG (OR: 7.30; p<0.001), highlighting the importance of gene–gene interactions in the expression of hyperTG.

Conclusions

In this study, the g.-469G>A polymorphism in the GPIHBP1 gene promoter was associated with an increased risk of hyperTG and had an additive effect on the risk conferred by LPL defective alleles.

Keywords: Hypertriglyceridemia, Polymorphism, GPIHBP1, Lipoprotein lipase, Gene-to-gene interaction

Abbreviations: apo, apolipoproprotein, CAD, coronary artery disease, CM, chylomicron, GPIHBP1, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1, GWAS, genome-wide association studies, HDL, high-density lipoprotein, hyperTG, hypertriglyceridemia, LD, linkage disequilibrium, LDL, low-density lipoprotein, LPL, lipoprotein lipase, MAF, minor allele frequency, NEFA, non-esterified fatty acids, OR, odds ratio, RR, relative risk, SLSJ, Saguenay-Lac-Saint-Jean, SNP, single nucleotide polymorphism, T2D, type 2 diabetes, TG, triglyceride, VLDL, very low-density lipoprotein